Skip main navigation

Pulmonary Effective Arterial Elastance as a Measure of Right Ventricular Afterload and Its Prognostic Value in Pulmonary Hypertension Due to Left Heart Disease

Originally publishedhttps://doi.org/10.1161/CIRCHEARTFAILURE.117.004436Circulation: Heart Failure. 2018;11:e004436

    Abstract

    Background:

    Patients with combined post- and precapillary pulmonary hypertension due to left heart disease have a worse prognosis compared with isolated postcapillary. However, it remains unclear whether increased mortality in combined post- and precapillary pulmonary hypertension is simply a result of higher total right ventricular load. Pulmonary effective arterial elastance (Ea) is a measure of total right ventricular afterload, reflecting both resistive and pulsatile components. We aimed to test whether pulmonary Ea discriminates survivors from nonsurvivors in patients with pulmonary hypertension due to left heart disease and if it does so better than other hemodynamic parameters associated with combined post- and precapillary pulmonary hypertension.

    Methods and Results:

    We combined 3 large heart failure patient cohorts (n=1036) from academic hospitals, including patients with pulmonary hypertension due to heart failure with preserved ejection fraction (n=232), reduced ejection fraction (n=335), and a mixed population (n=469). In unadjusted and 2 adjusted models, pulmonary Ea more robustly predicted mortality than pulmonary vascular resistance and the transpulmonary gradient. Along with pulmonary arterial compliance, pulmonary Ea remained predictive of survival in patients with normal pulmonary vascular resistance. The diastolic pulmonary gradient did not predict mortality. In addition, in a subset of patients with echocardiographic data, Ea and pulmonary arterial compliance were better discriminators of right ventricular dysfunction than the other parameters.

    Conclusions:

    Pulmonary Ea and pulmonary arterial compliance more consistently predicted mortality than pulmonary vascular resistance or transpulmonary gradient across a spectrum of left heart disease with pulmonary hypertension, including patients with heart failure with preserved ejection fraction, heart failure with reduced ejection fraction, and pulmonary hypertension with a normal pulmonary vascular resistance.

    Introduction

    WHAT IS NEW?

    • Pulmonary effective arterial elastance is associated with mortality in pulmonary hypertension (PH) due to left heart disease in both heart failure with preserved and reduced ejection fraction.

    • In the setting of PH due to left heart disease, pulmonary effective arterial elastance and pulmonary arterial compliance, parameters reflective of total right ventricular afterload, are more consistently associated with right ventricular (RV) dysfunction and prognosis than measures of precapillary disease (pulmonary vascular resistance, transpulmonary gradient, and diastolic pulmonary gradient).

    • The diastolic pulmonary gradient or combination of pulmonary vascular resistance >3 Wood units and diastolic pulmonary gradient ≥7 mm Hg did not predict prognosis in this study.

    WHAT ARE THE CLINICAL IMPLICATIONS?

    • This study confirms that measures of total RV afterload are more predictive of mortality and RV dysfunction in PH due to left heart disease than measures associated with precapillary PH.

    • Pulmonary effective arterial elastance could prove to be an attractive, noninvasive metric to measure total RV afterload and index ventricular function to RV afterload.

    • These findings add support to the idea that worse mortality in combined post- and precapillary PH is a result of higher total RV load. Therapies targeting total RV load rather than the precapillary component, many of which are aimed at treating the left ventricle in tandem with pulmonary vascular loading, may prove beneficial.

    Among patients with pulmonary hypertension due to left heart disease (PH-LHD), individuals with combined post- and precapillary PH (CpcPH) have worse prognosis compared with isolated postcapillary pulmonary hypertension.1,2 CpcPH is differentiated from isolated postcapillary PH hemodynamically by measures that suggest the presence of pulmonary vascular pathology, including pulmonary vascular resistance (PVR) ≥3 Wood units, transpulmonary gradient (TPG) ≥12 to 15 mm Hg, and diastolic pulmonary gradient (DPG) ≥7 mm Hg, and each has been associated with worse survival in various heart failure studies.1,35 However, isolated pressure measures (ie, TPG or DPG) do not incorporate flow (stroke volume), which may limit their prognostic value, and PVR (which does incorporate flow) only accounts for nonpulsatile afterload. In addition, it remains unclear whether patients with CpcPH simply have worse overall hemodynamics and higher total right ventricular (RV) load compared with isolated postcapillary PH, and therefore, if markers of total RV load better predict mortality.2 In the setting of left heart failure, pulmonary arterial compliance (PAC) is determined by both PVR and left heart filling pressures.6 Consistently, several studies have demonstrated it to be a superior prognostic marker compared with PVR.79 Pulmonary effective arterial elastance (Ea) is a lumped measure of RV afterload that more fully incorporates resistive, pulsatile, and passive components.10,11 We sought to determine whether pulmonary Ea as a measure of total RV load is associated with mortality in PH-LHD and compare its prognostic ability to hemodynamic markers of precapillary PH.

    Methods

    Patient Populations

    The combined patient cohort (A, B, and C) consisted of 1036 patients from 3 academic institutions. The data, analytic methods, and study materials will not be made available to other investigators.

    Cohort A: Johns Hopkins (Heart Failure With Reduced Ejection Fraction [HFrEF] and Heart Failure With Preserved Ejection Fraction [HFpEF])

    As previously reported,12 this cohort included 1236 patients referred to the Johns Hopkins Hospital Cardiomyopathy Service for evaluation of new cardiomyopathy between 1982 and 1997. Heart failure specialists performed all right heart catheterization procedures and interpreted the hemodynamic data. A complete set of hemodynamic data were available in 1174 patients. The patients were followed until death, cardiac transplantation, or the end of the study period (January 1, 1998). Participants who underwent transplantation were censored at the time of transplantation. Vital status was obtained from medical records and through a search of the Nation Death Index.13 The Johns Hopkins Hospital Joint Committee on Clinical Investigation approved the study. There were 193 events recorded in 1608 patient-years.

    Cohort B: Mayo Clinic Rochester (HFrEF)

    This cohort included 490 ambulatory outpatients with HFrEF (left ventricular ejection fraction ≤40%) referred to the Mayo Clinic (Rochester, MN) for a right heart catheterization between 2002 and 2008. Exclusion criteria were previously described14 and included patients with primary parenchymal lung disease, chronic obstructive pulmonary disease, prior valvular surgery, infiltrative, constrictive, or hypertrophic cardiomyopathy, myocardial infarction within 6 months, any history of group 1 (idiopathic, familial, collagen vascular disease, congenital heart disease), group 3 or group 4 (pulmonary thromboembolic disease) PH disease, tachyarrhythmia, chronic kidney disease, history of chest radiation, cardiac or lung transplantation. A complete set of hemodynamic data were available in 478 patients. Patient survival or all-cause mortality status was confirmed through June 30, 2010, using Mayo Clinic (Rochester, MN) electronic medical records, Olmsted County (MN) medical record linkage system, and Social Security mortality index. The Mayo Foundation Institutional Research Review Board approved the study and all patients included provided informed consent. There were 140 events recorded in 805 patient-years.

    Cohort C: Northwestern University (HFpEF)

    Four hundred twenty patients were enrolled prospectively between March 2008 and May 2011 from the outpatient clinic of the Northwestern University HFpEF Program. A total of 293 patients underwent invasive hemodynamic testing, and of those, 232 subjects met criteria for PH-LHD (defined below). All patients were recruited as outpatients after hospitalization for heart failure as previously reported,15 and all patients were enrolled into the study based on a left ventricular ejection fraction >50% and the presence of Framingham criteria for heart failure. Although not required for inclusion into the cohort, all patients had evidence of either significant diastolic dysfunction (grade 2 or 3) on echocardiography, evidence of elevated left ventricular filling pressures on invasive hemodynamic testing, or brain natriuretic peptide >100 pg/mL. All enrolled patients followed-up in a specialized HFpEF outpatient program. Patients with greater than moderate valvular disease, prior cardiac transplantation, history of reduced left ventricular ejection fraction <40% (ie, recovered EF), or diagnosis of constrictive pericarditis were excluded. All participants gave written informed consent, and the institutional review board at Northwestern University approved the study. There were 78 events recorded in 1144 patient-years.

    Hemodynamic Measures

    PH-LHD was defined as a mean pulmonary artery pressure (mPAP) ≥25 mm Hg with a pulmonary artery wedge pressure (PAWP) >15 mm Hg. Total RV load was estimated by pulmonary Ea. Historically, systemic Ea was initially derived using parameters from a 3-element arterial Windkessel model,16 but later was simplified to end-systolic pressure divided by stroke volume (SV) which can be readily obtained from a pressure–volume loop.10 This simplification was later validated in the RV.17 Under normal conditions, the RV ejects into a low impedance circuit, and pressure declines throughout ejection.18 Therefore, in the setting of normal afterload, end-systolic pressure is closely related to mPAP. However, with development of PH, the RV pressure–volume loop changes shape with pressure rising throughout ejection and peaking near end-systole. Therefore, in patients with PH, end-systolic pressure is more closely approximated by systolic pulmonary artery pressure (sPAP), and Ea can be defined as sPAP/SV.19,20 Because our cohort included only participants with PH, this latter definition of Ea (sPAP/SV) was used in all analyses. TPG was calculated as the difference between mPAP and PAWP and PVR as TPG divided by cardiac output. DPG was calculated as the difference between the diastolic pulmonary artery pressure and PAWP. PAC was estimated as stroke volume divided by pulmonary artery pulse pressure. Cardiac output was determined by either thermodilution or direct Fick technique in all 3 cohorts. These calculations are summarized in Table I in the Data Supplement.

    Statistical Analysis

    Continuous variables were compared across the 3 cohorts with 1-way ANOVA or Kruskal–Wallis if non-normally distributed. Categorical variables were compared with χ2 test. Hazard ratios (HRs) of death for PVR, TPG, DPG, PAC, and pulmonary Ea were estimated with Cox proportional hazards regression analysis (unadjusted and 2 adjusted models). We chose to adjust for only age in the first adjusted model given the known impact of aging on PAC and PVR.6 In the second model, we adjusted for age, body mass index, heart rate, sex, and cohort (cohort only in pooled analysis). We did not adjust for race because these data were not available in cohort B. We tested the proportionality assumption using scaled Schoenfeld residuals on time in each individual cohort and for each variable added to the Cox model. Survival was also estimated with the nonparametric methods of Kaplan and Meier and compared using the log-rank test. Qualitative data on RV function were available in cohorts B and C. Each subject was classified as having none, mild-moderate, or severe RV dysfunction. Those who had been reported as moderate-severe were considered severe for our analysis. The ability of Ea, PAC, PVR, TPG, and DPG to discriminate any RV dysfunction as well as severe RV dysfunction was assessed by calculating a C-statistic. A P value (2-tailed) of <0.05 was considered significant. Medians are presented with interquartile range. Statistical analyses were performed using STATA version 12 (Stata Corp, TX) and SigmaPlot version 11 (Systat Software Inc).

    Results

    Study Populations

    Clinical characteristics and hemodynamics for the combined cohort and each individual cohort is shown Table 1. Cohort A had the youngest patients among the 3 groups (P<0.001), had a high percentage of nonischemic cardiomyopathy, and included patients with higher heart rate than the other 2 cohorts. Cohort C had a higher percentage of female sex and higher body mass index than cohorts A and B. In contrast to cohorts A and B, cohort C (HFpEF) also had an overall better hemodynamic profile as evident by the higher cardiac index, PAC, RV stroke work index, left ventricular stroke work index, and lower pulmonary Ea and PVR when compared with the other 2 groups. Forty percent of cohort A (469 of 1174 subjects), 68% of cohort B (335 of 490 subjects), and 79% of cohort C (232 of 293 subjects) met invasive hemodynamic criteria for PH-LHD. PH-LHD was, therefore, present in 53% of the combined cohort.

    Table 1. Clinical Characteristics and Hemodynamics

    All Cohorts (n=1036)Cohort A (n=469)Cohort B (n=335)Cohort C (n=232)P Value
    Demographics
     Age, y57 [45 to 67]49 [34 to 64]59 [49 to 68]63 [57 to 71]<0.001
     Body mass index, kg/m227.7 [23.9 to 33.3]26.2 [19.1 to 33.4]28.4 [25.0 to 33.0]31.8 [26.0 to 38.4]<0.001
     Female sex400 (39)167 (36)89 (27)144 (61)<0.001*
     Race
      Black256 (37)169 (36)87 (38)
      White411 (59)289(62)NA122 (52)
      Other32 (4)9(2)23 (10)<0.001*
    Diagnosis
     Nonischemic557 (80)423 (90)NA134 (58)
     Ischemic144 (20)46 (10)NA98 (42)<0.001*
    Hemodynamics
     Heart rate, beats per minute81 [69 to 97]92 [75 to 111]75 [66 to 87]71 [63 to 80]<0.001
     Systemic blood pressure
      Systolic, mm Hg121 [106 to 139]118 [91 to 145]NA124 [112 to 138]0.097
      Diastolic, mm Hg75 [66 to 84]78 [62 to 94]NA70 [60 to 77]<0.001
      Mean, mm Hg90 [81 to 102]91 [73 to 109]NA87 [81 to 97]<0.001
     Systemic vascular resistance, Wood units18 [13 to 25]21 [12 to 30]NA12.3 [9.4 to 15.5]<0.001
     Left ventricular stroke work index, mm Hg mL/m21685 [1154 to 2510]1375 [654 to 2096]NA2595 [1886 to 3168]<0.001
     Right atrial pressure, mm Hg13 [9 to 18]11 [5 to 17]14.7 [10 to 19]15 [12 to 20]<0.001
     Pulmonary artery pressures
      Systolic, mm Hg53 [45 to 63]52 [40 to 64]54 [46 to 64]53 [45 to 66]0.038
      Diastolic, mm Hg27 [22 to 31]27 [21 to 33]26 [22 to 31]27 [23 to 33]0.051
      Mean, mm Hg35 [30 to 42]35 [27 to 43]36 [30 to 42]36 [30 to 43]0.130
     Pulmonary artery wedge pressure, mm Hg25 [20 to 35]25 [19 to 31]24 [20 to 28]25 [21 to 31]0.006
     Cardiac index, L/min per m22.2 [1.7 to 2.7]1.9 [1.3 to 2.5]2.0 [1.7 to 2.4]2.9 [2.4 to 3.4]<0.001
     Right ventricular stroke work index, mm Hg mL/m2598 [407 to 835]517 [275 to 761]629 [410 to 846]866 [612 to 1200]<0.001
     Pulmonary effective arterial elastance, mm Hg/mL1.0 [0.7 to 1.5]1.3 [0.6 to 2.0]1.0 [0.8 to 1.4]0.6 [0.5 to 0.9]<0.001
     Pulmonary artery compliance, mL/mm Hg2.0 [1.4 to 2.9]1.6 [0.7 to 2.6]1.9 [1.4 to 2.5]3.2 [2.4 to 4.7]<0.001
     Pulmonary vascular resistance, Wood units2.3 [1.4 to 3.5]2.4 [0.5 to 4.3]2.8 [1.8 to 4.1]1.7 [1.1 to 2.5]<0.001
     Transpulmonary gradient, mm Hg11 [7 to 14]9 [3.5 to 14.5]11 [7.0 to 15.3]10 [8.0 to 14.0]<0.001
    Diastolic pulmonary gradient, mm Hg1 [−1.0 to 5.0]1 [−3.9 to 5.9]1.3 [−1.0 to 5.0]0 [0 to 3.0]0.078
    RA/PAWP0.5 [0.3 to 0.7]0.4 [0.2 to 0.6]0.5 [0.4 to 0.70]0.6 [0.4 to 0.7]<0.001

    Data presented as median [interquartile range]. ANOVA or Kruskal–Wallis test unless otherwise indicated. () indicates percentage; NA, not applicable; PAWP; pulmonary artery wedge pressure; and RA, right atrial pressure.

    *χ2.

    Rank-sum test.

    Pulmonary Ea Is Associated With Mortality in Patients With PH-LHD

    In unadjusted and adjusted analyses, pulmonary Ea was significantly associated with increased mortality (adjusted1 HR per 1 mm Hg/mL increase in Ea, 1.47 [1.31–1.65]; χ2=44.3; P<0.001 and adjusted2 HR, 1.45 [1.27–1.65]; χ2=29.6; P<0.001; Table 2). Lower PAC, higher PVR, and higher TPG were also associated with increased mortality in age-adjusted analyses (PAC: adjusted1 HR per 1 mL/mm Hg decrease in PAC, 1.33 [1.22–1.45]; χ2=41.0; P<0.001 and adjusted2 HR, 1.30 [1.18–1.43]; χ2=29.3; P<0.001; PVR: HR per 1 Wood unit increase in PVR, 1.15 [1.10–1.20]; χ2=36.5; P<0.001; and adjusted2 HR, 1.14 [1.08–1.19]; χ2=27.8; P<0.001; TPG: adjusted1 HR per 1 mm Hg increase in TPG, 1.02 [1.00–1.03]; χ2=6.5; P=0.01; and adjusted2 HR, 1.02 [1.01–1.04]; χ2=8.2; P=0.004). Higher PAWP alone also tended to predict mortality: adjusted1 HR, 1.02 per 1 mm Hg increase, χ2=3.9, P=0.052 and adjusted2 HR, 1.03 [1.00–1.06], χ2=4.5, P=0.034. The median pulmonary Ea was 1.036 mm Hg/mL. Over a median follow-up of 2.8 years, mortality was significantly worse in those patients with an Ea higher than the median (P<0.001; Figure 1 [pooled cohort] and Figure I in the Data Supplement[individual cohorts]). Similar pooled data relative to median values is shown for PAC and PVR in Figure II in the Data Supplement.

    Table 2. Hazard Ratios for Hemodynamic Parameters

    All CohortsCohort ACohort BCohort C
    Hazard Ratio (95% CI) per Unit IncreaseP Valueχ2Hazard Ratio (95% CI) per Unit IncreaseP Valueχ2Hazard Ratio (95% CI) per Unit IncreaseP Valueχ2Hazard Ratio (95% CI) per Unit IncreaseP Valueχ2
    Ea
     Unadjusted1.41 (1.26–1.59)<0.00134.01.26 (1.06–1.51)0.0096.91.65 (1.23–2.22)0.00110.91.60 (1.13–2.27)0.0087.0
     Adjusted*1.47 (1.31–1.65)<0.00144.31.25 (1.08–1.49)0.0126.31.64 (1.22–2.20)0.00110.91.44 (0.99–2.10)0.0537.8
     Adjusted1.45 (1.27–1.65)<0.00129.61.30 (1.08–1.56)0.0057.81.72 (1.23–2.42)0.0029.81.47 (0.97–2.23)0.0693.3
    PAC
     Unadjusted1.30 (1.19–1.41)<0.00135.81.22 (1.03–1.45)0.0215.31.45 (1.18–1.82)0.00111.31.22 (1.06–1.41)0.0067.7
     Adjusted*1.33 (1.22–1.45)<0.00141.01.19 (1.02–1.41)0.0334.51.37 (1.11–1.72)0.0048.31.16 (1.01–1.35)0.0424.1
     Adjusted1.30 (1.18–1.43)<0.00129.31.26 (1.04–1.52)0.0175.61.37 (1.09–1.73)0.0077.21.15 (0.99–1.34)0.0763.2
    PVR
     Unadjusted1.16 (1.11–1.21)<0.00140.21.13 (1.06–1.20)<0.00112.91.12 (1.04–1.21)0.0029.31.18 (1.01–1.37)0.0354.4
     Adjusted*1.15 (1.10–1.20)<0.00136.51.10 (1.03–1.18)0.0048.41.11 (1.03–1.20)0.0077.31.11 (0.94–1.30)0.221.5
     Adjusted1.14(1.08–1.19)<0.00127.81.11 (1.04–1.19)0.0038.81.12 (1.03–1.21)0.0057.81.08 (0.92–1.28)0.360.8
    TPG
     Unadjusted1.02 (1.00–1.04)0.0038.81.02 (1.00–1.05)0.0255.01.01 (0.99–1.04)0.152.11.03 (0.99–1.06)0.171.9
     Adjusted*1.02 (1.00–1.03)0.0116.51.02 (1.00–1.05)0.0713.21.02 (0.99–1.04)0.122.41.02 (0.98–1.06)0.271.2
     Adjusted1.02 (1.01–1.04)0.0048.21.03 (1.00–1.05)0.0424.11.02 (1.00–1.05)0.0633.41.02 (0.98–1.06)0.271.2
    DPG
     Unadjusted1.01 (0.99–1.03)0.301.01.02 (1.00–1.05)0.0952.61.00 (0.97–1.03)0.900.10.98 (0.90–1.06)0.550.3
     Adjusted*1.01 (0.99–1.03)0.291.01.02 (0.99–1.05)0.122.21.01 (0.98–1.04)0.440.60.98 (0.90–1.06)0.660.2
     Adjusted1.01 (0.99–1.03)0.171.91.02 (1.00–1.05)0.0992.71.01 (0.99–1.04)0.360.80.99 (0.91–1.07)0.780.1

    The outcome is all-cause mortality. CI indicates confidence interval; DPG, diastolic pulmonary gradient; Ea, pulmonary effective elastance; HR, hazard ratio; PAC, pulmonary artery compliance; PVR, pulmonary vascular resistance; and TPG, transpulmonary gradient.

    *Adjusted model accounts for age.

    Adjusted model accounts for age, sex, body mass index, heart rate, and cohort.

    HRs are per 1-unit decrease in PAC.

    Figure 1.

    Figure 1. Kaplan–Meier survival curve of patients with heart failure in combined cohorts. In patients with pulmonary hypertension due to left heart disease (mean pulmonary artery pressure ≥25 mm Hg and pulmonary artery wedge pressure >15 mm Hg), higher pulmonary effective arterial elastance (Ea) discriminated survivors. The median pulmonary Ea for all 3 cohorts combined was used as a cutoff value. ***P<0.001.

    DPG Is Not Associated With Mortality in Patients With PH-LHD

    DPG was not associated with mortality in unadjusted or adjusted analyses nor was it using the guideline-recommended cutoff of ≥7 mm Hg (P=0.46; Figure 2A). CpcPH defined as DPG ≥7 mm Hg and PVR >3 WU trended toward worse survival compared with the rest of the cohort but did not reach statistical significance (P=0.086; Figure 2B).

    Figure 2.

    Figure 2. Kaplan–Meier survival curve of patients with heart failure in combined cohort.A, In patients with pulmonary hypertension due to left heart disease (PH-LHD; mean pulmonary artery pressure ≥25 mm Hg and pulmonary artery wedge pressure >15 mm Hg), diastolic pulmonary gradient (DPG) ≥7 mm Hg did not discriminate survivors. B, Similarly, in patients with PH-LHD DPG ≥7 mm Hg and pulmonary vascular resistance (PVR) >3 Wood units did not discriminate survivors.

    Pulmonary Ea and PAC Association With RV Dysfunction

    Qualitative data on RV function determined by echocardiography were available in cohorts B and C. In this combined cohort (B and C), pulmonary Ea and PAC discriminated more strongly severe RV dysfunction, as well as any RV dysfunction compared with PVR, TPG, and DPG (Table 3).

    Table 3. Hemodynamic Parameters and Right Ventricular Dysfunction

    C-Statistic for Severe RV DysfunctionC-Statistic for Any RV Dysfunction
    Ea0.780.72
    PAC0.780.71
    PVR0.670.65
    TPG0.520.52
    DPG0.520.51

    DPG indicates diastolic pulmonary gradient; Ea, pulmonary effective arterial elastance; PAC, pulmonary arterial compliance; PVR, pulmonary vascular resistance; RV, right ventricular; and TPG, transpulmonary gradient.

    Pulmonary Ea and PAC Are Associated With Mortality in Subjects With Normal PVR

    In the subset of subjects with normal PVR (n=685), 212 had an Ea above the median value for the larger cohort and 217 had a PAC below the median for the larger cohort. Pulmonary Ea (adjusted1 HR, 1.31 [1.04–1.66]; χ2=5.2; P=0.022; and adjusted2 HR, 1.34 [0.99–1.81]; χ2=3.6; P=0.057) and PAC (adjusted1 HR, 1.20 [1.09–1.33]; χ2=13.8; P<0.001 and adjusted2 HR, 1.22 [1.08–1.37]; χ2=11.0; P≤0.001) remained predictive of mortality when examining the subgroup of patients with PVR ≤3WU whereas PVR did not. PAWP by itself also did not predict mortality in this subset. We then divided the entire combined cohort into tertiles of PVR and plotted pulmonary Ea and PAC as a function of PAWP (Figure 3A and 3B). Pulmonary Ea increased and PAC decreased as PAWP increased in all PVR tertiles. Data for individual cohorts are shown in Figures III and IV in the Data Supplement. As illustrated in these figures, subjects in the 2 lower PVR tertiles have similar or even higher pulmonary Ea (or lower PAC) than the highest PVR tertile when PAWP is significantly elevated.

    Figure 3.

    Figure 3. Impact of PAWP on measures of right ventricular afterload.A, Distribution of pulmonary effective arterial elastance (Ea) values and their respective regression lines as a function of pulmonary artery wedge pressure (PAWP) into tertiles of pulmonary vascular resistance (PVR) in combined cohort of patients with pulmonary hypertension due to left heart disease. Pulmonary Ea increased as PAWP increased in all tertiles of PVR. When compared with the highest PVR tertile, the 2 lower PVR tertiles can have similar or even higher pulmonary Ea at significantly elevated PAWP levels. B, Distribution of pulmonary arterial compliance (PAC) as a function of PAWP into tertiles of PVR in the combined cohorts of patient with pulmonary hypertension due to left heart disease. Similarly, patients in the 2 lower PVR tertiles had similar or even lower PAC compared with the higher PVR tertile at significantly elevated PAWP.

    Discussion

    Main Findings

    In an analysis of a large combined cohort of patients with PH due to left heart disease, pulmonary Ea as a hemodynamic marker of total RV afterload was associated with mortality in patients with PH-LHD. Pulmonary Ea and PAC more consistently predicted mortality than PVR or TPG across a spectrum of left heart disease with PH, including patients with HFpEF and HFrEF, and were more strongly associated with RV dysfunction. Ea and PAC remained predictive of mortality in a subgroup of patients with normal resistive load. Last, DPG was not associated with mortality in this large combined cohort or in individual cohorts of HFrEF or HFpEF.

    RV function is a strong predictor of prognosis in both heart failure with preserved and reduced ejection fraction.21,22 The RV is more afterload sensitive (both acutely and chronically) than the left ventricle,11,23 and it is, therefore, not surprising that development of PH is itself associated with worse outcomes. Although PH with a precapillary component is associated with a worse prognosis than isolated postcapillary PH, those patients with a precapillary component also tend to have worse overall hemodynamics and higher total RV load. The gold standard for assessing RV afterload is pulmonary artery input impedance spectra which allows for assessment of total and individual components of afterload.24 Although resistive load (ie, PVR) makes up a substantial proportion of total RV load, other components, including PAC and arterial wave reflections, contribute as well. Ea incorporates these other factors and is an attractive hemodynamic marker because it can be derived from a standard right heart catheterization, therefore not requiring more invasive or sophisticated measurement techniques. This study confirms that measures of total RV afterload are more predictive of mortality and RV dysfunction in PH-LHD than measures associated with precapillary PH. Ghio et al25 recently showed significant vasoreactivity and reversibility of the precapillary component in those with CpcPH, suggesting a significant functional component to the precapillary parameters, including the DPG. One may speculate that this could explain, in part, why therapies targeting the precapillary component in LHD have yielded disappointing results. In a post hoc analysis of the RELAX study (Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure With Preserved Ejection Fraction), for example, sildenafil failed to significantly lower total RV afterload.26

    In absence of left heart failure and normal PAWP, RV pulsatile load is almost exclusively dependent on resistive load—which is unique compared with the systemic circulation—and therefore is generally a constant proportion of total RV load.27 However, in left heart failure, elevated left atrial pressure (ie, PAWP) has been shown in several studies to reduce PAC out of proportion to PVR, thereby increasing RV pulsatile loading.6,7,28,29 Thus, in the pulmonary circulation, compliance is also a lumped parameter that is determined by both resistive and pulsatile components of RV load. Similar to the findings in our study, Pellegrini et al29 showed that PAC remained a predictor of mortality even in subjects with LHD and normal PVR. In this situation, pulsatile loading makes up a higher proportion of total RV load. Because the pulmonary resistance–compliance relationship is steep when PVR is borderline or just mildly elevated, modestly lowering PVR in this setting may result in robust reductions in pulsatile load.6 For example, inorganic sodium nitrite, a novel nitric oxide-providing agent, increased PAC significantly despite only a modest reduction in resistive load in patients with HFpEF.30 This effect was also, in part, because of lowering PAWP.

    Importantly, the effects of pulsatile loading are reflected in the sPAP not diastolic pulmonary artery pressure. Because mPAP reflects both diastolic pulmonary artery pressure and sPAP, it is less reflective of pulsatile loading than sPAP. Indeed, in a recent study of subjects with HFpEF, sPAP was the only hemodynamic parameter associated with cardiac events in multivariate analysis.8 In addition, Wong et al9 showed that sPAP and heart rate were the 2 major determinants of RV myocardial oxygen consumption in a group of patients with idiopathic pulmonary arterial hypertension. In our study, Ea—which is estimated by sPAP/SV—and PAC—which is estimated by SV/(sPAP−diastolic pulmonary artery pressure)—were more predictive of mortality than measures incorporating mPAP (ie, PVR). It is also important to consider that Ea can be easily measured noninvasively using echocardiography by simply dividing estimated RV systolic pressure by stroke volume. This could prove to be an attractive, straightforward metric to measure total RV afterload noninvasively and index ventricular function to RV afterload.

    Finally, although DPG ≥7 mm Hg has been suggested as a diagnostic marker of CpcPH, the findings of this work along with other published data7,12,3133 call into question its use as a prognostic variable in PH-LHD. The European Society of Cardiology/European Respiratory Society PH Guidelines currently define CpcPH as DPG ≥7 mm Hg and/or PVR >3 WU. More recently, however, it has been suggested that this definition should be modified to DPG ≥7 mm Hg and PVR >3WU because DPG ≥7 mm Hg in the setting of a PVR <3 WU is likely related to measurement error or tachycardia.34 In the current study, the group fitting this definition trended toward worse outcome yet did not reach statistical significance. It remains to be seen if DPG may still be valuable as a marker to identify patients with PH-LHD who are responsive to pulmonary vasodilator therapy. Alternatively, therapies targeting total RV load rather than the precapillary component, many of which are aimed at treating the left ventricle in tandem with PA vascular loading,30 may be more appropriate.

    Strengths and Limitations

    A major strength of our study is the large sample size of the combined cohort but also that results were generally concordant among the 3 independent cohorts, thereby increasing the validity of our findings across the spectrum of ejection fraction in patients with heart failure and left heart disease. Specifically, cohort B (HFrEF) and cohort C (HFpEF) showed similar results. In addition, each of these 3 cohorts included invasive hemodynamic data that are the gold standard for diagnosing PH-LHD.

    We do acknowledge that our analysis has several limitations. First, our retrospective study was composed of 3 cohorts from 3 different hemodynamic laboratories, and different heart failure cardiologists performed all measurements and interpreted the hemodynamic tracings. Therefore, variation in data analysis might be present. Despite the different operators and patient characteristics, the fact that our results were generally consistent among all 3 cohorts is reassuring. Although we controlled for cohort in our pooled analysis, there is still the potential of pooled estimates to accentuate confounding and inflate the effect estimate. Information on heart failure therapies, including medications, laboratory values, and comorbidities, such as chronic obstructive pulmonary disease, atrial fibrillation, and renal failure, were not available in all cohorts nor where pulmonary vascular pathology samples. Echocardiography was only available in 2 of the cohorts, and only qualitative assessment of RV function was available for our study. Although patients with left heart failure may have elevated PVR, TPG, or DPG, significant pulmonary vascular remodeling may be absent in many left heart disease patients based on the relative quick reversal of PH seen after transplant or implant of a mechanical assist device.35 In those heart failure patients with definite pulmonary vascular disease, such as that seen in pulmonary arterial hypertension, it remains possible that precapillary markers of PH have additive value. Last, because Ea and PAC incorporate the contributions of elevated left heart pressures, they are not likely to be useful in defining precapillary disease for diagnostic purposes.

    Conclusions

    In conclusion, our study shows that in PH due to left heart failure, higher pulmonary Ea and lower PAC are associated with mortality and RV dysfunction. These parameters were more consistently associated with mortality across the spectrum of heart failure and even when resistive load was normal. These findings add support to the idea that worse mortality in CpcPH is a result of higher total RV load.

    Footnotes

    http://circheartfailure.ahajournals.org

    The Data Supplement is available at http://circheartfailure.ahajournals.org/lookup/suppl/doi:10.1161/CIRCHEARTFAILURE.117.004436/-/DC1.

    Ryan J. Tedford, MD, Medical University of South Carolina, Thurmond Gazes Building, 30 Courtenay Dr, BM215/MSC592, Charleston, SC 29435. E-mail

    References

    • 1. Vachiéry JL, Adir Y, Barberà JA, Champion H, Coghlan JG, Cottin V, De Marco T, Galiè N, Ghio S, Gibbs JS, Martinez F, Semigran M, Simonneau G, Wells A, Seeger W. Pulmonary hypertension due to left heart diseases.J Am Coll Cardiol. 2013; 62(suppl 25):D100–D108. doi: 10.1016/j.jacc.2013.10.033.CrossrefMedlineGoogle Scholar
    • 2. Guazzi M, Borlaug BA. Pulmonary hypertension due to left heart disease.Circulation. 2012; 126:975–990. doi: 10.1161/CIRCULATIONAHA.111.085761.LinkGoogle Scholar
    • 3. Cappola TP, Felker GM, Kao WH, Hare JM, Baughman KL, Kasper EK. Pulmonary hypertension and risk of death in cardiomyopathy: patients with myocarditis are at higher risk.Circulation. 2002; 105:1663–1668.LinkGoogle Scholar
    • 4. Gerges C, Gerges M, Lang MB, Zhang Y, Jakowitsch J, Probst P, Maurer G, Lang IM. Diastolic pulmonary vascular pressure gradient: a predictor of prognosis in “out-of-proportion” pulmonary hypertension.Chest. 2013; 143:758–766. doi: 10.1378/chest.12-1653.CrossrefMedlineGoogle Scholar
    • 5. Naeije R, Vachiery JL, Yerly P, Vanderpool R. The transpulmonary pressure gradient for the diagnosis of pulmonary vascular disease.Eur Respir J. 2013; 41:217–223. doi: 10.1183/09031936.00074312.CrossrefMedlineGoogle Scholar
    • 6. Tedford RJ, Hassoun PM, Mathai SC, Girgis RE, Russell SD, Thiemann DR, Cingolani OH, Mudd JO, Borlaug BA, Redfield MM, Lederer DJ, Kass DA. Pulmonary capillary wedge pressure augments right ventricular pulsatile loading.Circulation. 2012; 125:289–297. doi: 10.1161/CIRCULATIONAHA.111.051540.LinkGoogle Scholar
    • 7. Al-Naamani N, Preston IR, Paulus JK, Hill NS, Roberts KE. Pulmonary arterial capacitance is an important predictor of mortality in heart failure with a preserved ejection fraction.JACC Heart Fail. 2015; 3:467–474. doi: 10.1016/j.jchf.2015.01.013.CrossrefMedlineGoogle Scholar
    • 8. Aschauer S, Kammerlander AA, Zotter-Tufaro C, Ristl R, Pfaffenberger S, Bachmann A, Duca F, Marzluf BA, Bonderman D, Mascherbauer J. The right heart in heart failure with preserved ejection fraction: insights from cardiac magnetic resonance imaging and invasive haemodynamics.Eur J Heart Fail. 2015. 66:1308–1310.Google Scholar
    • 9. Wong YY, Westerhof N, Ruiter G, Lubberink M, Raijmakers P, Knaapen P, Marcus JT, Boonstra A, Lammertsma AA, van der Laarse WJ, Vonk-Noordegraaf A. Systolic pulmonary artery pressure and heart rate are main determinants of oxygen consumption in the right ventricular myocardium of patients with idiopathic pulmonary arterial hypertension.Eur J Heart Fail. 2011; 13:1290–1295. doi: 10.1093/eurjhf/hfr140.CrossrefMedlineGoogle Scholar
    • 10. Kelly RP, Ting CT, Yang TM, Liu CP, Maughan WL, Chang MS, Kass DA. Effective arterial elastance as index of arterial vascular load in humans.Circulation. 1992; 86:513–521.LinkGoogle Scholar
    • 11. Tedford RJ. Determinants of right ventricular afterload (2013 Grover Conference series).Pulmonary Circ. 2014; 4:211–219.CrossrefMedlineGoogle Scholar
    • 12. Tampakakis E, Leary PJ, Selby VN, De Marco T, Cappola TP, Felker GM, Russell SD, Kasper EK, Tedford RJ. The diastolic pulmonary gradient does not predict survival in patients with pulmonary hypertension due to left heart disease.JACC Heart Fail. 2015; 3:9–16. doi: 10.1016/j.jchf.2014.07.010.CrossrefMedlineGoogle Scholar
    • 13. Boyle CA, Decouflé P. National sources of vital status information: extent of coverage and possible selectivity in reporting.Am J Epidemiol. 1990; 131:160–168.CrossrefMedlineGoogle Scholar
    • 14. Miller WL, Grill DE, Borlaug BA. Clinical features, hemodynamics, and outcomes of pulmonary hypertension due to chronic heart failure with reduced ejection fraction: pulmonary hypertension and heart failure.JACC Heart Fail. 2013; 1:290–299. doi: 10.1016/j.jchf.2013.05.001.CrossrefMedlineGoogle Scholar
    • 15. Shah SJ, Katz DH, Selvaraj S, Burke MA, Yancy CW, Gheorghiade M, Bonow RO, Huang CC, Deo RC. Phenomapping for novel classification of heart failure with preserved ejection fraction.Circulation. 2015; 131:269–279. doi: 10.1161/CIRCULATIONAHA.114.010637.LinkGoogle Scholar
    • 16. Sunagawa K, Maughan WL, Burkhoff D, Sagawa K. Left ventricular interaction with arterial load studied in isolated canine ventricle.Am J Physiol. 1983; 245(5pt 1):H773–H780. doi: 10.1152/ajpheart.1983.245.5.H773.MedlineGoogle Scholar
    • 17. Morimont P, Lambermont B, Ghuysen A, Gerard P, Kolh P, Lancellotti P, Tchana-Sato V, Desaive T, D’Orio V. Effective arterial elastance as an index of pulmonary vascular load.Am J Physiol Heart Circ Physiol. 2008; 294:H2736–H2742. doi: 10.1152/ajpheart.00796.2007.CrossrefMedlineGoogle Scholar
    • 18. Maughan WL, Shoukas AA, Sagawa K, Weisfeldt ML. Instantaneous pressure-volume relationship of the canine right ventricle.Circ Res. 1979; 44:309–315.LinkGoogle Scholar
    • 19. Vanderpool RR, Pinsky MR, Naeije R, Deible C, Kosaraju V, Bunner C, Mathier MA, Lacomis J, Champion HC, Simon MA. RV-pulmonary arterial coupling predicts outcome in patients referred for pulmonary hypertension.Heart. 2015; 101:37–43. doi: 10.1136/heartjnl-2014-306142.CrossrefMedlineGoogle Scholar
    • 20. Metkus TS, Mullin CJ, Grandin EW, Rame JE, Tampakakis E, Hsu S, Kolb TM, Damico R, Hassoun PM, Kass DA, Mathai SC, Tedford RJ. Heart rate dependence of the pulmonary resistance x compliance (RC) time and impact on right ventricular load.PLoS One. 2016; 11:e0166463. doi: 10.1371/journal.pone.0166463.CrossrefMedlineGoogle Scholar
    • 21. Ghio S, Gavazzi A, Campana C, Inserra C, Klersy C, Sebastiani R, Arbustini E, Recusani F, Tavazzi L. Independent and additive prognostic value of right ventricular systolic function and pulmonary artery pressure in patients with chronic heart failure.J Am Coll Cardiol. 2001; 37:183–188.CrossrefMedlineGoogle Scholar
    • 22. Melenovsky V, Hwang SJ, Lin G, Redfield MM, Borlaug BA. Right heart dysfunction in heart failure with preserved ejection fraction.Eur Heart J. 2014; 35:3452–3462. doi: 10.1093/eurheartj/ehu193.CrossrefMedlineGoogle Scholar
    • 23. Newman JH, Brittain EL, Robbins IM, Hemnes AR. Effect of acute arteriolar vasodilation on capacitance and resistance in pulmonary arterial hypertension.Chest. 2015; 147:1080–1085. doi: 10.1378/chest.14-1461.CrossrefMedlineGoogle Scholar
    • 24. Nichols WW, O’Rourke MF, Hartley C, McDonald DAMcDonald’s Blood Flow in Arteries: Theoretic, Experimental, and Clinical Principles. 4th ed. London, United Kingdom: Arnold andNew York, NY: Oxford University Press; 1998.Google Scholar
    • 25. Ghio S, Crimi G, Temporelli PL, Traversi E, La Rovere MT, Cannito A, Vizza D, Scelsi L, Raineri C, Guazzi M, Oltrona Visconti L. Haemodynamic effects of an acute vasodilator challenge in heart failure patients with reduced ejection fraction and different forms of post-capillary pulmonary hypertension [published online ahead of print November 16, 2017].Eur J Heart Fail. doi: 10.1002/ejhf.1067. https://onlinelibrary.wiley.com/doi/abs/10.1002/ejhf.1067.Google Scholar
    • 26. Borlaug BA, Lewis GD, McNulty SE, Semigran MJ, LeWinter M, Chen H, Lin G, Deswal A, Margulies KB, Redfield MM. Effects of sildenafil on ventricular and vascular function in heart failure with preserved ejection fraction.Circ Heart Fail. 2015; 8:533–541. doi: 10.1161/CIRCHEARTFAILURE.114.001915.LinkGoogle Scholar
    • 27. Saouti N, Westerhof N, Helderman F, Marcus JT, Boonstra A, Postmus PE, Vonk-Noordegraaf A. Right ventricular oscillatory power is a constant fraction of total power irrespective of pulmonary artery pressure.Am J Respir Crit Care Med. 2010; 182:1315–1320. doi: 10.1164/rccm.200910-1643OC.CrossrefMedlineGoogle Scholar
    • 28. Dupont M, Mullens W, Skouri HN, Abrahams Z, Wu Y, Taylor DO, Starling RC, Tang WH. Prognostic role of pulmonary arterial capacitance in advanced heart failure.Circ Heart Fail. 2012; 5:778–785. doi: 10.1161/CIRCHEARTFAILURE.112.968511.LinkGoogle Scholar
    • 29. Pellegrini P, Rossi A, Pasotti M, Raineri C, Cicoira M, Bonapace S, Dini FL, Temporelli PL, Vassanelli C, Vanderpool R, Naeije R, Ghio S. Prognostic relevance of pulmonary arterial compliance in patients with chronic heart failure.Chest. 2014; 145:1064–1070. doi: 10.1378/chest.13-1510.CrossrefMedlineGoogle Scholar
    • 30. Borlaug BA, Melenovsky V, Koepp KE. Inhaled sodium nitrite improves rest and exercise hemodynamics in heart failure with preserved ejection fraction.Circ Res. 2016; 119:880–886. doi: 10.1161/CIRCRESAHA.116.309184.LinkGoogle Scholar
    • 31. Tedford RJ, Beaty CA, Mathai SC, Kolb TM, Damico R, Hassoun PM, Leary PJ, Kass DA, Shah AS. Prognostic value of the pre-transplant diastolic pulmonary artery pressure-to-pulmonary capillary wedge pressure gradient in cardiac transplant recipients with pulmonary hypertension.J Heart Lung Transplant. 2014; 33:289–297. doi: 10.1016/j.healun.2013.11.008.CrossrefMedlineGoogle Scholar
    • 32. Palazzini M, Dardi F, Manes A, Bacchi Reggiani ML, Gotti E, Rinaldi A, Albini A, Monti E, Galiè N. Pulmonary hypertension due to left heart disease: analysis of survival according to the haemodynamic classification of the 2015 ESC/ERS guidelines and insights for future changes.Eur J Heart Fail. 2018; 20:248–255. doi: 10.1002/ejhf.860.CrossrefMedlineGoogle Scholar
    • 33. Mazimba S, Kennedy JL, Zhuo D, Bergin J, Abuannadi M, Tallaj J, Bilchick KC. Decreased pulmonary arterial proportional pulse pressure after pulmonary artery catheter optimization for advanced heart failure is associated with adverse clinical outcomes.J Card Fail. 2016; 22:954–961. doi: 10.1016/j.cardfail.2016.03.019.CrossrefMedlineGoogle Scholar
    • 34. Guazzi M, Naeije R. Pulmonary hypertension in heart failure: pathophysiology, pathobiology, and emerging clinical perspectives.J Am Coll Cardiol. 2017; 69:1718–1734. doi: 10.1016/j.jacc.2017.01.051.CrossrefMedlineGoogle Scholar
    • 35. Masri SC, Tedford RJ, Colvin MM, Leary PJ, Cogswell R. Pulmonary arterial compliance improves rapidly after left ventricular assist device implantation.ASAIO J. 2017; 63:139–143. doi: 10.1097/MAT.0000000000000467.CrossrefMedlineGoogle Scholar